EP3750538B1 - Non-hormonal methods for male contraception comprising (r)-silodosin - Google Patents

Non-hormonal methods for male contraception comprising (r)-silodosin Download PDF

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Publication number
EP3750538B1
EP3750538B1 EP20182691.4A EP20182691A EP3750538B1 EP 3750538 B1 EP3750538 B1 EP 3750538B1 EP 20182691 A EP20182691 A EP 20182691A EP 3750538 B1 EP3750538 B1 EP 3750538B1
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composition
silodosin
use according
alpha
male
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German (de)
English (en)
French (fr)
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EP3750538A1 (en
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Guillaume El Glaoui
Mehdi El Glaoui
Philippe Perrin
Stéphane DROUPY
Véronique AGATHON-MERIAU
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Pharmajor International
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Pharmajor International
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/16—Masculine contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • the present invention relates to non-hormonal compositions and methods for male contraception. More specifically, this invention relates to a method of inducing a reversible condition of aspermia, azoospermia or severe oligozoospermia in a male subject, sufficient for a continuous contraceptive effect.
  • compositions and methods for female contraception have been well known in the art for decades, the same cannot be said for male contraception.
  • the high demand for such a product is based upon the individual needs of each male subject, and may include, for example, the desire or need to reduce the burden of oral hormonal contraception on any female partner, or to minimize the possibility of failures associated with female contraception. Notwithstanding this demand, development of contraceptive pharmaceutical compositions and methods for men has proven to be a major medical challenge.
  • contraceptives are female contraceptives. Only few options exist for men wishing to assume the birth control responsibility, which amount mainly to the use of prophylactics, such as condoms. The numerous drawbacks of condoms are well-known in the field, and include both potential for failure (i.e., breaking or improper use) as well as a decrease in sexual sensation.
  • Another contraceptive option available to men is the surgical option of having a vasectomy, a procedure in which the male vas deferens are severed and then tied or sealed in a manner so as to prevent sperm from entering into the urethra.
  • a vasectomy is typically considered to be a permanent method of sterilization, and is not easily reversed, and so is not a viable option for any male subject who wishes to have children at any point in the future.
  • Hormonal contraceptive methods have other drawbacks as well, including, for example, the requirement of high dosage amounts ( Guerin et al, INTERNATIONAL JOURNAL OF ANDROLOGY, 1988, 11 (3), 187-199 ) or frequent injection schedules ( World Health Organization Task Force on Methods for the Regulation of Male Fertility, FERTIL. STERIL., 1996, 65(4), 821-829 ).
  • alpha-1-adrenoceptors The male urinary smooth muscles contain high densities of alpha-1-adrenoceptors and several alpha-1-adrenoceptor subtypes have been identified, namely alpha-1a, alpha-1b and alpha-1d-adrenoceptor subtypes.
  • the alpha-1a-adrenoceptor subtype has been described to be predominant in the human prostate and is present in the male reproductive tract tissues (testis, epididymis, seminal vesicle and prostate) ( Patr ⁇ o et al, MHR-BASIC SCIENCE OF REPRODUCTIVE MEDECINE, 2008, 14 (2), 85-96 ).
  • Alpha-1-adrenoreceptor antagonists make up a class of drugs that blocks alpha1-adrenergic receptors in arteries, smooth muscles, and central nervous system tissues. When administered in humans, they prevent the hormone norepinephrine from tightening the muscles in the walls of smaller arteries and veins, which causes the vessels to remain open and relaxed. This improves blood flow and lowers blood pressure. Because alpha blockers also relax other muscles throughout the body, these medications can help improve urine flow in older men with prostate problems such as Benign Prostatic Hyperplasia ("BPH").
  • BPH Benign Prostatic Hyperplasia
  • alpha-1 adrenoceptor antagonists may induce negative side effects such as hypotension, blepharoptosis, rhinorrhea, fatigue, headaches or diarrhea.
  • the alpha-1-adrenoreceptor antagonist tamsulosin is sold commercially as tamsulosin hydrochloride, ((-)-( R )-5-[2-[[2-(o-Ethoxyphenoxy) ethyl]amino]propyl]-2- methoxy-benzenesulfonamide, monohydrochloride) under the trade name, e.g., Flomax ® for the treatment of BPH.
  • Flomax ® for the treatment of BPH.
  • Silodosin also known as (-)-( R )-1-(3-hydroxypropyl)-5-[2-[[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl]amino]propyl]indoline-7-carboxamide, is a highly selective alpha-1a-adrenoreceptor antagonist that is also currently known and used in the treatment of BPH. Currently, it is marketed and sold as a BPH treatment under the brand name Urorec ® or Rapaflo ® .
  • silodosin when administered in amounts to treat BPH, is retrograde ejaculation (RE), also known as a decrease or absence of semen during ejaculation.
  • RE retrograde ejaculation
  • Sakata K. et al. demonstrated that the administration of silodosin at 4 mg twice a day induced ejaculatory disorder at a high incidence ( K. Sakata et al., BMC Urology 2012, 12:29 ).
  • Kobayashi et al. reported that 4 mg of silodosin given twice a day for 3 days, induced a complete lack of seminal emission on healthy volunteers ( Kobayashi et al., International Journal of Impotence Research 2009, 21, 306-310 ).
  • Kobayashi et al. also show a 100% rate of discomfort upon ejaculation for male subjects treated with silodosin ( Kobayashi K, et al. Inhibition of seminal emission is the main cause of anejaculation induced by a new highly selective ⁇ 1A-blocker in normal volunteers.
  • J. SEX MED (2008) 5:2185-2190 while Shimizu et al. report a decrease in quality of orgasm ( Shimizu F, et al. Impact of dry ejaculation caused by highly selective alpha1a-blocker: randomized, double-blind, placebo-controlled crossover pilot study in healthy volunteer men. J. SEX MED. (2010) 7(3):1277-83 ).
  • alpha-1 especially alpha-1a blockers on the ejaculatory function as well as their side effects is known to be dose-dependent (see e.g., Hisasue SI, et al. Ejaculatory disorder caused by alpha-1 adrenoceptor antagonists is not retrograde ejaculation but a loss of seminal emission. INTERNATIONAL JOURNAL OF UROLOGY (2006) 13:1311-1316 ).
  • Bhat et al does not fulfill the needs of the subjects who ask for a safe contraceptive method ensuring a continuous contraceptive effect, where they are confident that they are not exposed to a fertility risk.
  • the present invention aims at bringing a solution to those subjects. Especially, the present invention aims at providing compositions and methods would not impact the erectile function, sexual desire, ejaculation, and quality of orgasm, of the male subject nor induce undesirable side effects that would discourage male subjects from using it.
  • This invention aims at providing a composition for use in a male contraceptive method, where side effects are highly limited, administration is simple, effect is reversible, and as in female contraception, when a delay occurs, compared to the recommended administration scheme, such delay does not impair the effectiveness.
  • a treatment method shall resemble to female hormonal contraceptive methods where a once-a-day pill is to be administered at the same time every day and a subject's delay in taking one pill for as long as twenty-four-hours does not impact the contraceptive effect.
  • alpha-1 adrenoceptor antagonists especially alpha-1a adrenoceptor antagonists, could meet all the requirements and criteria of a continuous male contraceptive method that would be suitable for a large population without much restrictions, altogether.
  • the Applicant shows that, in a subject implementing the method of the invention, the quality of orgasm and the erectile function are preserved, as shown by the unchanged numerical rating scale (NRS) score for subjective quality of orgasms and unchanged international index of erectile function (IIEF): a multidimensional scale for assessment of erectile dysfunction.
  • NRS numerical rating scale
  • IIEF international index of erectile function
  • compositions for use in a non-hormonal contraception method for a male subject wherein said composition is an extended release formulation comprising:
  • the intake of a next dose can be delayed from 6 to 18 hours after the last regular daily dose time, and the condition of aspermia, azoospermia or severe oligozoospermia is maintained in the male subject.
  • failure to intake one daily dose does not affect the continuous state of aspermia, azoospermia or severe oligozoospermia supporting the contraception method for 36 to 48 hours as of the last intake time.
  • the contraception method is carried on for at least eight days.
  • (R)-silodosin is in a polymorphic or amorphous form.
  • the composition includes or consists of at least one particle, preferably at least one coated particle, and the average particle diameter is in the range of 0.01 to 5 mm, preferably 0.1 to 2 mm.
  • the particles are encompassed into a capsule, each capsule being filled by particles in a number sufficient to reach the daily dose.
  • the contraception is achieved independently from the food consumption by the male subject.
  • the daily administration contraception method further comprises a simultaneous or sequential administration of an additional composition suitable for treating erectile dysfunction; preferably the additional composition comprises a phosphodiesterase-5 inhibitor.
  • the initial period of consecutive days is at least two consecutive days, with administration at about the same time each day. According to one embodiment, the initial period of consecutive days is at least 5 days. According to one embodiment, the method is suitable for short term, at least 8 days, to long term treatment. According to one embodiment, successive daily doses may be missed or omitted such that no dose is administered for more than about 48 hours.
  • two successive daily doses can be missed or omitted without affecting contraceptive effect in the male subject.
  • the amount of alpha-1-adrenoreceptor antagonist in the composition administered once daily is about 4 to about 12 mg. According to one embodiment, the amount of (R)-silodosin in the composition administered once daily is about 4 to about 12 mg. According to one embodiment, the amount of (R)-silodosin in the composition administered once daily is about 8 mg.
  • the composition is simultaneously or sequentially co-administered with a composition suitable for treating erectile dysfunction; preferably the additional composition comprises a phosphodiesterase-5 (PDE5) inhibitor.
  • the male subject suffers from benign prostatic hyperplasia (BPH).
  • BPH benign prostatic hyperplasia
  • the male subject suffers from BPH and erectile dysfunction.
  • the composition is administered with food.
  • the composition is administered without food.
  • the extended release formulation comprises a microgranule form.
  • the microgranules are less than 2 millimeters in diameter.
  • the microgranules have a density greater than or equal to about 1.
  • compositions comprising composition
  • This invention relates to the use of a composition in a non-hormonal contraception method for a male subject, the composition comprising an alpha-1-adrenoreceptor antagonist, wherein the alpha-1-adrenoreceptor is silodosin; and a pharmaceutically acceptable carrier.
  • the non-hormonal contraception method includes a once-a-day administration of the composition according to the present invention. In order to maintain an effective exposure to the male subject, the contraception method is carried out for at least two days.
  • This once-a-day administration induces a contraceptive effect resulting from triggering aspermia, azoospermia, or severe oligozoospermia in the male subject for at least 24 hours.
  • the contraceptive effect obtained by the once-a-day administration of the composition of the invention is not affected by a delay of the consecutive once-a-day administration, supposed to occur 24 hours after the former administration, said delay not exceeding 6 hours after first administration, and said delay not exceeding 24 hours after further administration.
  • the contraceptive effect obtained by the once-a-day administration of the composition of the invention is not reversed by a delay of the consecutive once-a-day administration, said delay not exceeding 6 hours after first administration, and said delay not exceeding 24 hours after further administration.
  • the daily administration of the alpha-1-adrenoreceptor antagonist is made at about the same time on each day. In this particular embodiment, about means two hours before or after the same time.
  • the daily administration contraception method is a single daily administration contraception method.
  • the use of the composition as previously described comprises a biologically effective amount of alpha-1-adrenoreceptor antagonist.
  • the biologically effective amount of alpha-1 adrenoreceptor antagonist can be determined by a person skilled in the art based on his general knowledge, the pharmacokinetic parameters of the alpha-1 adrenoreceptor antagonist, the subject's age, health condition etc.
  • the alpha-1-adrenoreceptor antagonist is comprised in the composition in the amount from about 4 to about 30 mg, preferably from about 4 to about 20 mg.
  • the therapeutic dose of the alpha-1-adrenoreceptor antagonist (alpha blocker) used in any of the dosage forms described or referred to herein may be or include, by way of example only, about 0.1 mg, about 0.2 mg, about 0.4 mg, about 0.8 mg, about 1 mg, about 2 mg, about 4 mg, about 6 mg, about 8 mg, about 10 mg, about 12 mg, about 16 mg, about 20 mg. about 24 mg, about 26 mg, or about 30 mg.
  • Embodiments of the compositions' formulation administrated in the invention's use may be, include, or resemble a variety of dosage forms that are well known in the art.
  • this may include capsules, tablets, caplets, soft shell capsules, gel caplets (gel-caps), liquid compositions, powders, concentrated powders, concentrated powders admixed with liquids, chewable forms, swallowable forms, water soluble films, granulated forms, pellet forms, and oral liquid suspensions.
  • composition can be into a single day oral dosage forms selected from the group consisting of: soft-gels, caplets, pills, tablets, microtablets, capsules, hydromatrix tablets, and osmotic tablets.
  • excipients may be found in WADE & WELLER, HANDBOOK OF PHARMACEUTICAL EXCIPIENTS (2nd ed. 1994). All active ingredients, fillers and excipients are commercially available from companies such as Aldrich Chemical Co., FMC Corp, Bayer, BASF, Alexi Fres, Witco, Mallinckrodt, Rhodia, ISP, and others.
  • the excipients used in the orally dissolvable compositions fall into several functional categories and may include, by way of example, plasticizers, emulsifiers, taste enhancers, sweeteners, and flavoring agents. Additionally, or alternatively, excipients may be of the type used in other FDA-approved oral contraceptive products.
  • the non-hormonal contraceptive compositions comprise one or more inactive ingredients.
  • the inactive ingredients may comprise one or more of the following: sugar, corn starch, water, gelatin, citric acid, lactic acid, one or more glazing agents (e.g., vegetable oil, beeswax, carnauba wax), one or more natural flavors (e.g., plum, apple, mixed berry, cherry), one or more natural colors (e.g., black carrot), and one or more masking flavors (e.g., tartaric acid, menthol).
  • glazing agents e.g., vegetable oil, beeswax, carnauba wax
  • natural flavors e.g., plum, apple, mixed berry, cherry
  • one or more natural colors e.g., black carrot
  • masking flavors e.g., tartaric acid, menthol
  • the non-hormonal contraceptive compositions may comprise one or more inactive ingredients that include but are not limited to water, buffers (including, by way of example and without limitation, phosphate buffers, citrate buffers, lactic acid, and others known to those of ordinary skill in the art), stabilizing agents (including, by way of example and without limitation, antioxidants (e.g., ascorbic acid, propionic acid, sodium bisulfite, sodium sulfite, and the like), chelating agents (e.g., fumaric acid, sodium edetate, and the like), and others known to those of ordinary skill in the art), surfactants (including, by way of example and without limitation, wetting agents (e.g., sorbitan monolaurate, etc.), antifoaming agents (e.g., sorbitan trioleate, etc.), detergents (e.g., sucrose stearate, etc.), solubilizing agents (e.g., polyethylene glycol 400 monostearate,
  • FD&C Red No. 20 FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, FD&C Orange No. 5, D&C Red No. 8, caramel, ferric oxide red, pigments, dyes, tints, titanium dioxide, natural coloring agents, such as grape skin extract, red beet powder, beta carotene, annato, carmine, turmeric, paprika, black carrot juice, and others known to those of ordinary skill in the art
  • sweeteners or sweetening agents including, by way of example and without limitation, sucrose, fructose, , high fructose corn syrup, dextrose, saccharin sodium, maltodextrin, aspartame, potassium acesulfame, neohesperidin dihydrochalcone, sucralose, monoammonium glycyrrhizinate, and others known to those of ordinary skill in the art
  • perfuming agents including, by way of example and without limitation, natural flavor oil, natural vanilla
  • a male subject's delay in intake, or failure to intake, of one (or more) dose(s) would not nullify the contraceptive effect of the treatment regimen, and would also allow a day-to-day adjustment to a more convenient intake time.
  • the daily administration of the alpha-1-adrenoceptor antagonist can be delayed as of the third day of two consecutive daily intakes with no impact on the contraceptive effect on the male subject, such delay not exceeding 2, 4, 6, 8, 10 12, 16, 20 or 24 hours from the day-before uptake time, preferably not exceeding 2, 4, 6 hours from the day-before uptake time.
  • the daily administration of the alpha-1-adrenoceptor antagonist can be delayed as of the fourth day of three consecutive daily intakes with no impact on the contraceptive effect on the male subject, such delay not exceeding 2, 4, 6, 8, 10 12, 16, 20 or 24 hours from the day-before uptake time.
  • the daily administration of the alpha-1-adrenoceptor antagonist can be delayed as of the fifth day of four consecutive daily intakes with no impact on the contraceptive effect on the male subject, such delay not exceeding 2, 4, 6, 8, 10 12, 16, 20 or 24 hours from the day-before uptake time.
  • the daily administration of the alpha-1-adrenoceptor antagonist can be delayed as of the sixth day of five consecutive daily intakes with no impact on the contraceptive effect on the male subject, such delay not exceeding 2, 4, 6, 8, 10 12, 16, 20 or 24 hours from the day-before uptake time.
  • the daily administration of the alpha-1-adrenoceptor antagonist can be delayed as of the seventh day of six consecutive daily intakes with no impact on the contraceptive effect on the male subject, such delay not exceeding 2, 4, 6, 8, 10 12, 16, 20 or 24 hours from the day-before uptake time.
  • the once-a-day administration contraception method is carried out for at least two days. In one embodiment, the once-a-day administration contraception method is carried out for at least three days. In one embodiment, the once-a-day administration contraception method is carried out for at least for at least four days. In one embodiment, the once-a-day administration contraception method is carried out for at least for at least five. In one embodiment, the once-a-day administration contraception method is carried out for at least six days.
  • the delay of a subsequent daily administration does not exceed 2, 4, 6, 8, 10 12, 16, 20 or 24 hours from the day-before uptake time. In one embodiment, the delay does not exceed 2, 4, 6, 8, 10 12, 16, 20 or 24 hours from the day-before uptake time. In one embodiment, the delay does not exceed 2 hours from the day-before uptake time. In one embodiment, the delay does not exceed 4 hours from the day-before uptake time. In one embodiment, the delay does not exceed 6 hours from the day-before uptake time. In one embodiment, the delay does not exceed 8 hours from the day-before uptake time. In one embodiment, the delay does not exceed 10 hours from the day-before uptake time. In one embodiment, the delay does not exceed 12 hours from the day-before uptake time. In one embodiment, the delay does not exceed 16 hours from the day-before uptake time. In one embodiment, the delay does not exceed 20 hours from the day-before uptake time. In one embodiment, the delay does not exceed 24 hours from the day-before uptake time.
  • the contraceptive effect may be designed to withstand a delayed intake of 6 hours (e.g., contraceptive effect maintained up to 24 hours, and an additional six hour-delay, for a total of 30 hours post-dose).
  • this duration of action is longer, and the daily administration of the alpha-1- adrenoceptor antagonist can be delayed as of the first, second, third, fourth, fifth or sixth daily administration.
  • the dosage form is self-administered.
  • the dosage form may be enteral, particularly oral, buccal or sublingual. Oral, buccal, sublingual or transdermal administration may be discretely carried out without need for any external device.
  • the dosage form may comprise granules in a hard capsule containing a biologically effective amount of an alpha-1-adrenoreceptor antagonist to guarantee the contraception during a targeted duration.
  • the granules may comprise (i) an inert core, (ii) a drug layer applied to the inert core, comprising the alpha-1-adrenoreceptor antagonist and a binder, and (iii) a controlled release coating surrounding the drug layer.
  • Further embodiments of the invention may also comprise, optionally, a surfactant in combination with item (ii).
  • the granules may be matrix granules of an alpha-1-adrenoreceptor antagonist surrounded by controlled release coating and filled in a capsule, such as for example a hard capsule.
  • the granules can be compressed into a tablet.
  • the compositions described in this paragraph, including methods for preparing them, are well known in the pharmaceutical arts. WADE & WELLER, HANDBOOK OF PHARMACEUTICAL EXCIPIENTS (2nd ed. 1994 ); REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY (21st ed. 2005 ).
  • formulations to be used in the methods of the invention may further be, include, or resemble tablets or microtablets in a hard capsule, a coated tablet, a hydromatrix tablet, or an osmotic tablet containing a biologically effective amount of the alpha-1-adrenoreceptor antagonist to guarantee the contraception during a targeted duration.
  • Embodiments of the invention may therefore comprise tablets, specifically, matrix tablets of the alpha-1-adrenoreceptor antagonist surrounded by controlled release coating, and filled in a hard capsule.
  • the tablets can optionally be coated by a controlled release coating prior to their formulation into a tablet.
  • the obtained tablet may further be coated by a controlled release coating.
  • a coated tablet may be or comprise a matrix tablet of the alpha-1-adrenoreceptor antagonist surrounded by controlled release coating.
  • compositions administrated in the use according to the present invention are formulated in forms comprising granules or tablets.
  • the granules or tablets may optionally be coated by a controlled release coating.
  • the granules or tablets, as previously described, can be further filled into a capsule that optionally comprises a controlled release coating.
  • the composition is in a multiparticulate form.
  • a capsule may then be filled with the previously described particles or granules.
  • the sufficient number of these particles or granules within the capsule is determined by a person skilled in the art in view of reaching to daily dose of the alpha-1-adrenoreceptor antagonist.
  • the contraceptive effect resulting from triggering aspermia, azoospermia, or severe oligozoospermia and the absence of undesired side effects in the male subject is achieved independently from the food consumption by the male subject.
  • contraceptive effect resulting from triggering aspermia, azoospermia, or severe oligozoospermia in the male subject has the same efficacy and/or safety profile independently from the food consumption by the male subject.
  • the composition comprising the alpha-1-adrenoreceptor antagonist includes or consists of at least one particle, preferably at least one coated particle, and the average particle diameter is in the range of 0.01 to 5 mm, preferably 0.1 to 2 mm.
  • embodiments of the invention may comprise unitary dosage forms such as granules or tablets in a capsule that are released in the stomach.
  • sufficiently small size for instance, e.g. , with a diameter ⁇ 5 mm, preferably ⁇ 2 mm
  • the granules or tablets are not retained in the stomach with the food.
  • the usual food effect seen for silodosine-which relies upon a delayed voiding of the stomach in the presence of food-does not impact such formulations.
  • the average diameter of the particles ranges from 0.01 to 5 mm, preferably from 0.1 to 2 mm.
  • the particles as previously described are encompassed into a capsule, each capsule being filled by particles in a number sufficient to reach the daily dose.
  • the granules or tablets may also be designed with a specific density in order to avoid the food effect. If the density of the granules or tablets is too low, they will float at the top of the gastric fluids contained in the stomach during a fasting state, delaying transit to the intestine. Accordingly, in embodiments of the invention, the target density of the granules or tablets may be designed to avoid the floating phenomenon. In embodiments of the invention, a density ranging from about 1 to about 1.6 may be desirable. However, those skilled in the art will appreciate that other densities may be appropriate or ideal.
  • a hydromatrix tablet may also be used as a dosage form, particularly, e.g., a single or multiple-layer tablet comprising an alpha-1-adrenoreceptor antagonist and a hydrophilic excipient.
  • the compositions described in this paragraph, including methods for preparing them, are well known in the pharmaceutical arts. ( Peter Timmins,Samuel R. Pygall,Colin D. Melia. Hydrophilic Matrix Tablets for Oral Controlled Release (2014 ), Rumondor ACF et al. Minitablets: Manufacturing, Characterization Methods, and Future Opportunities. July 30, 2016 . Nokhodchi A. The Role of Oral Controlled Release Matrix Tablets in Drug Delivery Systems. BioImpacts (2012) 2(4):175-187 ).
  • alpha-1-adrenoreceptor antagonist alpha-1-adrenoreceptor antagonist
  • composition implemented in the present invention comprises silodosin as an alpha-1-adrenoreceptor antagonist.
  • the alpha-1-adrenoreceptor antagonist is ( R )-Silodosin.
  • the alpha-1-adrenoreceptor antagonist is ( R )-Silodosin in a polymorphic or amorphous form.
  • the non-hormonal compositions may also allow for consumption with or without food.
  • alpha-1 blockers may be administered with food in order to decrease the peak of their plasma concentration and consequently limit the occurrence of the cardiovascular side effects.
  • a so-called "food effect” is known to impact the pharmacokinetic profile of traditional formulations of (R)-Silodosin, leading to a delayed T max and lower C max .
  • the use of the composition offers an effective exposure for about 30 hours allowing maintenance of the contraceptive effect
  • the single daily oral dosage form comprises about 12 mg of alpha-1-adrenoreceptor antagonist; and said composition provides a pharmacokinetic profile of alpha-1-adrenoreceptor antagonist having:
  • the single daily oral dosage form comprises about 8 mg of alpha-1-adrenoreceptor antagonist; said composition provides a pharmacokinetic profile of alpha-1-adrenoreceptor antagonist having:
  • a dose of a consecutive day administration may be delayed within twenty-four hours (for, by way of example only, about 1, about 2, about 3, about 4, about 6, about 8, about 10, about 12, about 15, about 18, or about 21 hours) without impacting or altering the contraceptive effect of the composition.
  • a dose may be missed or omitted such that no dose is administered for more than about 24 hours (for, by way of example only, about 24, about 36, about 48, about 60, about 72, about 84, or about 96 hours).
  • Embodiments of the invention therefore include methods and compositions of administering an alpha-1-adrenoreceptor antagonist, or more in particular silodosin, which do not, or not significantly, impair the quality of orgasm for the male subject (often measured by the Numerical Rating Scale, NRS, for the quality of orgasm).
  • Other potential side effects which the claimed invention would avoid or maintain at a minimum include discomfort upon ejaculation, decreased sexual desire, feelings of reduced virility, ejaculation distress, decreased satisfaction, undesirable decrease or increase in intravaginal ejaculation latency time, or premature ejaculation.
  • the alpha-1-adrenoreceptor antagonist or silodosin in particular is present either alone, or in association with another active agent, or in combination with another active agent.
  • the alpha-1-adrenoreceptor antagonist as previously described may be included or used in the non-hormonal contraceptive compositions in any specific form just described.
  • the non-hormonal contraceptive compositions may include or use a combination of an alpha-1-adrenoreceptor antagonists as previously described or other components in the ranges or amounts as generally known in the art.
  • the use of the composition in the daily administration contraception method further comprises a simultaneous or sequential administration of an additional composition.
  • the additional composition is related or not related to the sexual health of the male subject.
  • the additional composition does not affect the cardiovascular system of the male subject.
  • the additional composition affects the cardiovascular system of the male subject. More in particular, the additional composition may induce the lowering of the male subject arterial pressure.
  • the safety profile of the present inventions male contraceptive method allows the simultaneous or sequential administration of an additional composition that may lower the patient's arterial pressure, with no risk of a hypotensive crisis.
  • Phosphodiesterase type 5 (PDE5) inhibitors are a class of drugs used in the treatment of erectile dysfunction having as an adverse effect the lowering of the subjects blood pressure.
  • Embodiments of the invention may comprise the co-administration of PDE5 inhibitors and ( R )-Silodosin in male patients suffering from erectile dysfunction and wanting to follow a male contraception method.
  • use of the composition in the daily administration contraception method further comprises a simultaneous or sequential administration of an additional composition suitable for treating erectile dysfunction; preferably the additional composition comprises a phosphodiesterase-5 inhibitor.
  • PDE5 inhibitors are mild vasodilators associated with small decreases in blood pressure.
  • Alpha-blockers are also well known vasoactive compounds.
  • the co-administration of PDE5 inhibitors and alpha-blockers may, under some circumstances, result in additive vasodilatory effect, particularly within patient populations likely to be prescribed PDE5 inhibitors in clinical practice.
  • ER (R)-Silodosin formulation with a decreased alpha blocker C max . Because the cardiovascular side effects of alpha blockers are related to their C max , an ER (R)-Silodosin formulation would likely minimize the potential for additive side effects during co-administration with PDE5 inhibitors.
  • the median T max of (R)-Silodosin L is about 2 hours ( CDER, NDA 22-206, CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS REVIEWS. Jul 2008 ).
  • the C max of each compound is not reached in the same time so that the cumulative effect is lower.
  • the C max is lower than in traditional/IR formulations of ( R )-Silodosin and the T max is delayed further apart from the T max of its associated PDE5 inhibitor.
  • alpha-adrenoreceptor antagonist extended release formulations allow the simultaneous or sequential administration of an additional composition that may lower the patient's arterial pressure, with no risk of a hypotensive crisis.
  • the alpha-adrenoreceptor antagonist is the alpha-1-adrenoreceptor antagonist ( R )-Silodosin.
  • the extended release formulations are adapted according to the general knowledge of the skilled artisan.
  • the extended release formulations are the extended release formulations according to the present invention.
  • embodiments of the invention may comprise the co-administration of PDE5 inhibitors and ( R )-Silodosin in extended release formulations for the treatment of male patients suffering from both pathologies.
  • various active ingredients may be incorporated into multiple compositions as a kit.
  • the non-hormonal contraceptive compositions disclosed herein may be packaged as kits using materials known to those of ordinary skill in the art.
  • kits may further include, by way of example, one or more back-up methods of birth control provided in the event that it is needed.
  • embodiments of the invention may comprise a composition formulated to maintain a contraceptive effect in a male subject for about 30 hours.
  • the packaging may be packaged in a sachet or package.
  • a packaging may comprise one or more individual dosage forms.
  • each packaging may comprise two individual dosage forms.
  • each packaging may comprise three individual dosage forms.
  • a unit dosage form may be individually wrapped, packaged as multiple units on paper strips, preferably blisters, or in vials of any size, without limitation.
  • the unitary doses are individually removable oral dosage units comprising the composition to be implemented according to the invention.
  • the orally dissolvable compositions of the invention may be packaged in unit dose, rolls, bulk bottles, and combinations thereof, without limitation.
  • the invention also relates to a packaging of unitary doses of the composition of the invention.
  • the composition includes alpha-1-adrenoreceptor antagonist in an amount ranging from about 0.1 to about 30 mg, preferably from about 0.2 to about 20 mg, preferably the alpha-1-adrenoreceptor antagonist is ( R )-silodosin in an amount of 8 to 12 mg.
  • the male contraceptive packaging comprises at least one packaging unit; wherein said packaging unit comprises from about 7 to about 30 separately packaged unitary doses of the composition as described in the present invention.
  • the male contraceptive packaging comprises from about 7 to about 28 unitary doses.
  • the male contraceptive packaging may comprise 7, 14, 28, 56 or 84 unitary doses.
  • the male contraceptive packaging may be suitable for longer periods of the non-hormonal male contraception method of the present invention.
  • the male contraceptive packaging comprises 7, 14, 28, 56, 84 or 168 to 365 unitary doses of the composition as described in the present invention.
  • the male contraceptive packaging comprises from about 10 to about 30 unitary doses.
  • the male contraceptive packaging may comprise 10, 20, 30, 60 or 90 unitary doses.
  • the male contraceptive packaging may be suitable for longer periods of the non-hormonal male contraception method of the present invention.
  • the male contraceptive packaging comprises 10, 20, 30, 60, 90 or 180 to 360 unitary doses of the composition as described in the present invention.
  • the unitary doses are placed in at least one blister.
  • the male contraceptive packaging is adequately labeled and may further comprise instructions for the male contraception method according to the present invention.
  • This example relates to extended release formulations of (R) -Silodosin.
  • Controlled release granules of (R) -Silodosin are prepared in accordance with the present invention as follows.
  • (R) -Silodosin is suspended in an aqueous solution of hydroxypropylmethyl cellulose (Opadry ⁇ ) and potassium phosphate monobasic (KH 2 PO 4 ).
  • the composition of the (R) -Silodosin suspension in detailed in table 1.
  • Table 1 (R) -Silodosin suspension composition % w/w Silodosin 9.60 HPMC (Opadry ⁇ ) 10.00 KH 2 PO 4 0.68 Purified water 79.72
  • the coated granules are further coated by spraying with an aqueous extended release coating solution of ethylcellulose (ECD Aquacoat ® , 25.25 % w/w), dibutylsebaccate (DBS, 1.89 % w/w) and guar gum (0.53 % w/w).
  • ECD Aquacoat ® 25.25 % w/w
  • DBS dibutylsebaccate
  • guar gum 0.53 % w/w
  • Table 4 Table 4.
  • the average particle size was less than 2 mm and the average density thereof was superior to 1.
  • Hard capsules were filled with the adequate quantity of formulation A to a final content of 8 and 12 mg per capsule.
  • the dissolution rate of the extended release formulation is slowed down compared to that of the reference immediate release formulations, such as for example Rapaflo ® or Urorec ® .
  • a study is undertaken to evaluate the effectiveness of the compositions of the present invention in the treatment of male subjects.
  • the objective of the study is to determine whether oral intake of an (R) -Silodosin results in a contraceptive effect.
  • the pharmacokinetic properties of (R) -Silodosin is modeled based on plasma concentration-versus-time profiles obtained after a single administration of 8 mg of (R) -Silodosin to healthy volunteers.
  • (R)- Silodosin data are described by a bi-compartment model with a first-order input rate constant.
  • the pharmacokinetic properties of (R) -Silodosin were measured on the basis of observed plasma concentrations. The observed plasma concentrations validate the plasma concentration simulation methods for (R) -Silodosin.
  • a contraception is maintained up to 24 h after the administration of a 12-mg single dose of (R) -Silodosin.
  • the C24 is the ( R) -Silodosin plasma concentration 24 hours post-dose.
  • a dosing regimen maintaining ( R) -Silodosin plasma concentrations significantly above C24 results in a continuous contraception.
  • Maintaining the ( R) -Silodosin concentration at a level at least equal to C24 should be sufficient; however, due to the variability of the pharmacokinetic properties of ( R) -Silodosin and the individual metabolism variability, it is important to provide a significant security margin (ie., minimum ( R) -Silodosin concentration significantly higher than C24).
  • the model is used to simulate the pharmacokinetic properties of (R) -Silodosin after at least two to at least five daily administrations of 8 mg of ( R) -Silodosin. After the administration of the (R) -Silodosin formulation A, the (R) -Silodosin plasma concentrations are constantly above C24, as presented in figure 2 .
  • the maximal plasma concentration (Cmax) is inferior to the Cmax measured past the administration of immediate release 8 mg ( R) -Silodosin formulations where the risk of orthostatic hypotension is considered acceptable by health authorities.
  • formulation A The administration of 8 and 12 mg (R) -Silodosin extended release formulations according to formulation A allows maintaining the contraception all along the once daily treatment, including in case of delayed intake and in case of a single omission.
  • the administration according to the present invention is able to maintain the contraception all along the treatment duration, including in case of delayed or omitted intake.

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IL319287A (en) 2022-11-23 2025-04-01 Pharmajor Incorporated Silodosin formulations with different release and their use in male contraceptive methods

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US4210644A (en) 1978-02-23 1980-07-01 The Johns Hopkins University Male contraception
DE4308406C1 (de) 1993-03-12 1994-06-16 Jenapharm Gmbh Kombinationspräparat zur Kontrazeption
ATE474580T1 (de) 2000-02-15 2010-08-15 Bayer Schering Pharma Ag Zusammensetzung zur männlichen kontrazeption, norethisteron enthaltend
FR2861990B1 (fr) * 2003-11-10 2006-02-10 Nouveaux Produits Pharma Comprimes faiblement doses a reseau de polymeres
UA95085C2 (ru) * 2005-09-29 2011-07-11 Баер Шеринг Фарма Акциенгезельшафт Применение варденафила для лечения урологических расстройств
JP2009509984A (ja) * 2005-09-29 2009-03-12 バイエル・ヘルスケア・アクチェンゲゼルシャフト 泌尿器系障害の処置用のｐｄｅ阻害剤およびそれらの組合せ
US20100098735A1 (en) * 2006-10-05 2010-04-22 Rajesh Jain Injectable depot compositions and its process of preparation
GB0700893D0 (en) 2007-01-17 2007-02-21 King S College London Male contraceptive
MX2009009230A (es) 2007-02-28 2009-11-26 Kissei Pharmaceutical Uso de silodosina en una administracion diaria para tratar hiperplasia prostatica benigna.
US20120184591A1 (en) * 2011-01-13 2012-07-19 Watson Pharmaceuticals, Inc. Methods for treating prostatitis
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WO2014118606A2 (en) * 2013-01-29 2014-08-07 Alembic Pharmaceuticals Limited A novel process for the preparation of silodosin
WO2016051782A1 (ja) 2014-09-30 2016-04-07 キッセイ薬品工業株式会社 苦味を有する薬剤の苦味をマスキングした経口投与製剤
US20170049834A1 (en) * 2015-08-18 2017-02-23 Golden Biotechnology Corporation Benign prostatic hyperplasia add-on therapy
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